title: Histamine h2 receptor signaling in the pathogenesis of sepsis: studies in a murine diabetes model.
abstract: Type 1 diabetes enhances susceptibility to infection and favors the sepsis development. In addition, diabetic mice produced higher levels of histamine in several tissues and in the blood after LPS stimulation than nondiabetic mice. In this study, we aimed to explore the role of mast cells (MCs) and histamine in neutrophil migration and, consequently, infection control in diabetic mice with mild sepsis (MS) induced by cecum ligation and puncture. We used female BALB/c, MC-sufficient (WB/B6), MC-deficient (W/W(v)), and NOD mice. Diabetic mice given MS displayed 100% mortality within 24 h, whereas all nondiabetic mice survived for at least 5 d. The mortality rate of diabetic mice was reduced to 57% after the depletion of MC granules with compound 48/80. Moreover, this pretreatment increased neutrophil migration to the focus of infection, which reduced systemic inflammatory response and bacteremia. The downregulation of CXCR2 and upregulation of G protein-coupled receptor kinase 2 in neutrophils was prevented by pretreatment of diabetic mice given MS with compound 48/80. In addition, blocking the histamine H2 receptor restored neutrophil migration, enhanced CXCR2 expression, decreased bacteremia, and improved sepsis survival in alloxan-induced diabetic and spontaneous NOD mice. Finally, diabetic W/W(v) mice had neutrophil migration to the peritoneal cavity, increased CXCR2 expression, and reduced bacteremia compared with diabetic WB/B6 mice. These results demonstrate that histamine released by MCs reduces diabetic host resistance to septic peritonitis in mice.
authors.affiliation: Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, 14049-900 Ribeirão Preto, São Paulo, Brazil.
authors.forename: Daniela
authors.initials: D
authors.lastname: Carlos
authors.forename: Fernando
authors.initials: F
authors.lastname: Spiller
authors.forename: Fabrício O
authors.initials: FO
authors.lastname: Souto
authors.forename: Silvia C
authors.initials: SC
authors.lastname: Trevelin
authors.forename: Vanessa F
authors.initials: VF
authors.lastname: Borges
authors.forename: Andressa
authors.initials: A
authors.lastname: de Freitas
authors.forename: José C
authors.initials: JC
authors.lastname: Alves-Filho
authors.forename: João S
authors.initials: JS
authors.lastname: Silva
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha
mesh_terms: D000496:Alloxan; D000818:Animals; D016470:Bacteremia / Q000188:drug therapy; D002465:Cell Movement; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000382:microbiology / Q000401:mortality*; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000378:metabolism*; D006632:Histamine / Q000378:metabolism; D006635:Histamine H2 Antagonists; D007249:Inflammation / Q000188:drug therapy; D008407:Mast Cells / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D009504:Neutrophils / Q000378:metabolism*; D011970:Receptors, Histamine H2 / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000378:metabolism*; D018805:Sepsis / Q000150:complications / Q000382:microbiology / Q000401:mortality; D015854:Up-Regulation / Q000187:drug effects; D003189:p-Methoxy-N-methylphenethylamine / Q000494:pharmacology
chemical_list: D006635:Histamine H2 Antagonists; D011970:Receptors, Histamine H2; D023063:Receptors, Interleukin-8B; D003189:p-Methoxy-N-methylphenethylamine; D000496:Alloxan; D006632:Histamine; C496568:GRK2 protein, mouse; D054769:G-Protein-Coupled Receptor Kinase 2